The goal of our research is to study the long-term (minutes to hours) adjustments of the nervous system to the environment and the role of the genome of brain cells in these adaptations. We are presently studying the influence of circulating hormones, specifically gonadal steroids as mediators of various types of neural plasticity occurring in adult life and during development. This work is relevant to fertility control and to certain nervous and mental disorders: eg., recovery from brain damage; Parkinson's disease; tardive dyskinesia; depressive illness and Alzheimers' disease. Also, sex differences in incidence of nervous and mental disease and in response to drugs may be linked, in part, to sex differences in the neurochemical substrate. The specific aims of this research are to explore the actions of estradiol (E) and progesterone (P) on specific hypothalamic nuclei which are implicated in the control of sexual behavior and ovulation in the rat. These studies have enable us to specify temporal characteristics of the hormonal stimuli during which RNA and protein synthesis are occurring. Moreover, we have begun to uncover sex differences in the systems subserving sexual behavior which may help us shed some light on the process of sexual differentiation. We plan to examine,, in terms of hormone receptors and genomic activity, the synergism between E and P and the sex differences in the actions of these two hormones. Steroid hormone autoradiography will be used as well as procedure for labeling specific brain nuclei in vitro with radioactive RNA and protein precursors, followed by 2 dimensional gel separations of labeled proteins and specific cDNA probes for detection of specific RNA's. We also plan to examine the role of cholinergic mechanisms in relation to the genomic actions of E on sexual differentiation and sexual behavior. Quantitative neurotransmitter receptor autoradiography (QAR) as well as microenzyme assays will be combined with local implantation of muscarinic drugs and specific lesions of cholinergic nuclei to assess the role of cholinergic function and the influence of E and P on the cholinergic system of the hypothelamus and basal forebrian. Finally, we plan to study other aspects of the CNS actions of E beginning with the effects of E to up-regulate serotonin receptors in a number of brain regions. These studies will also utilize QAR. Because E regulation of serotonin receptors differs between males and females, we ahsll attempt to reverse the sex difference by perinatally blocking or mimicking the actions of testosterone.